CN111938158B - 一种防止肠道Akkermansia muciniphila菌丰度降低的组合物 - Google Patents
一种防止肠道Akkermansia muciniphila菌丰度降低的组合物 Download PDFInfo
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- CN111938158B CN111938158B CN202010831740.5A CN202010831740A CN111938158B CN 111938158 B CN111938158 B CN 111938158B CN 202010831740 A CN202010831740 A CN 202010831740A CN 111938158 B CN111938158 B CN 111938158B
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- akkermansia muciniphila
- valine
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- intestinal
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Abstract
本发明涉及一种调节肠道嗜黏蛋白艾克曼菌(Akkermansia muciniphila)丰度的组合物，其由L‑缬氨酸与制剂辅料组成，通过向肠道补充一定量的L‑缬氨酸从而实现防止肠道Akkermansia muciniphila丰度降低的效果。通常，患有炎症性肠病、肥胖症患者体内的Akkermansia muciniphila含量会降低，本发明的组合物以补充L‑缬氨酸的方式可以恢复Akkermansia muciniphila的丰度从而改善代谢状态。本发明的组合物可以作为恢复Akkermansia muciniphila丰度的食品、保健品或者药物。
Description
技术领域
本发明涉及大健康领域，特别涉及大健康领域下的食品、保健品和药物领域，尤其是调节肠道微生物技术领域，具体涉及一种调节肠道嗜黏蛋白艾克曼菌(Akkermansiamuciniphila)丰度的组合物。
背景技术
人类的肠道微生物在健康和疾病之间扮演了重要角色。微生物菌群失调与各种代谢紊乱有关。Akkermansia muciniphila是一种革兰氏阴性的厌氧球菌。2004年，德里安教授和她的团队将其在人体肠道中分离出来，命名为Akkermansia muciniphila[DerrienM.Akkermansia muciniphila gen.nov.sp.nov.a human intestinal mucin-degradingbacterium.Int.J.Syst.Evol.Microbiol.2004,54]。
肠道中低水平的Akkermansia muciniphila可能导致黏膜层的变薄，从而导致肠道屏障功能减弱，使肠道内的毒素更容易侵入人体[Brahe et al.Specific gutmicrobiota features and metabolic markers in postmenopausal women withobesity.Nutrition&Diabetes,5(6):e159]。通常，患有炎症性肠病、肥胖症的患者都会出现体内Akkermansia muciniphila含量降低的情况。早期小鼠的研究表明，肥胖小鼠的Akkermansia muciniphila丰度降低，喂养益生元可以使Akkermansia muciniphila丰度正常化，从而改善小鼠的代谢状态[Everard A et al.Cross-talk between Akkermansiamuciniphila and intestinal epithelium controls diet-inducedobesity.Proceedings of the National Academy of Sciences,2013,110(22):9066-9071]。
目前通过益生元调节肠道菌群结构是主要的改善肠道微生态结构的方法。一般认为益生元给益生菌提供“食物”，益生元能够被肠道内有益细菌分解吸收，促进有益细菌生长繁殖。然而，由于很多种肠道益生菌对常见益生元的亲和性都非常相近，因此益生元的使用会使大量菌群的数量改变，无法靶向增殖某一种或某一类的益生菌。常见益生元的使用会使拟杆菌门/厚壁菌门降低，这将伴随着引起快速肥胖，长期使用有引起高血糖、高血脂、高血压等内分泌-代谢疾病的风险。
因此通过益生元来调节肠道Akkermansia muciniphila丰度的方法存在专一性差且可能会引起肥胖及其他疾病等缺陷。
发明内容
针对现有技术中存在的缺陷，本发明提出通过补充L-缬氨酸来恢复Akkermansiamuciniphila的丰度，与益生元调节Akkermansia muciniphila丰度的方法不同的是，L-缬氨酸是被肠道吸收，而不是被肠道菌群吸收，生物安全性高，故本发明的组合物可以作为恢复Akkermansia muciniphila丰度的食品、保健品或者药物。
本发明的目的在于提供一种防止Akkermansia muciniphila丰度降低的组合物，所述的组合物以L-缬氨酸为药效成分，对防止肠道Akkermansia muciniphila丰度降低有显著疗效。
为了实现以上目的，本发明提供了以下技术方案：
一种防止肠道Akkermansia muciniphila丰度降低的组合物，由L-缬氨酸与制剂辅料组成。缬氨酸是必需氨基酸，在现有技术中多用于营养增补剂，并没有将其用于防止肠道Akkermansia muciniphila丰度降低的相关报道。
进一步，本发明组合物中的药效成分L-缬氨酸可以为水溶性化合物，因此适用的剂型广泛，可根据产品用途(药用、保健或食品)以及消费人群来选择剂型，每种剂型的优缺点不同。
以口服液为例，口服液具有剂量小、吸收较快、质量稳定、携带和服用方便、易于保存的优点，在口服液中添加辅料可以提高口感，改善澄清度，增强稳定性，提高产品质量。
口服液常用辅料为溶剂、芳香剂、矫味剂、澄清剂和防腐剂中一种或多种。
以片剂为例，片剂具有剂量准确，质量稳定，服用、携带及运输方便等优点。
片剂常用辅料为为稀释剂、粘合剂、润滑剂和崩解剂中一种或多种。
以颗粒剂为例，颗粒剂可以直接吞服，也可以用温水冲入水中饮入，应用和携带比较方便，溶出和吸收速度较快。
颗粒剂常用辅料为填充剂、粘合剂、润湿剂、崩解剂、润滑剂和薄膜包衣材料中的一种或多种。
以胶囊剂为例，胶囊主要提高药物的稳定性和生物利用度。
胶囊剂常用辅料为硬胶囊壳或软胶囊壳。
本发明的组合物还可制成散剂。散剂便于分剂量和服用。
以饮料为例，将本发明的组合物制成不同风味的饮料，作为日常饮品将深受欢迎。
饮料常用辅料为澄清剂、防腐剂和香味剂中的至少一种。
本发明的组合物也可制成其它散剂，例如制成功能性奶粉，加入的辅料主要为奶粉，例如脱脂奶粉，脱脂无糖奶粉。
综上，与现有技术相比，本发明达到了以下技术效果：
(1)使用本发明的组合物可以通过补充L-缬氨酸来治疗或预防炎症性肠病和肥胖症，为炎症性肠病和肥胖症的治疗和预防提供新产品；
(2)本发明所提供的组合物能防止肠道Akkermansia muciniphila丰度降低，相比于益生元调节肠道Akkermansia muciniphila丰度的方法，具有专一性强和安全性高的优点；
(3)适用范围广，可用于食品、药品或保健品等众多领域；
(4)适用的剂型广泛，便于推广。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为小鼠粪便菌群16S rRNA测序的Akkermansia muciniphila的丰度分析，数据乘以10000后用对数处理的Akkermansia muciniphila丰度热图。
图2为小鼠粪便菌群16S rRNA测序的Akkermansia muciniphila的丰度分析，3组不同喂养方式的Akkermansia muciniphila的丰度占整体微生物丰度的百分比。*和**分别表示t检验P＜0.05和P＜0.01，具有显著性差异。N.S.表示没有显著性差异。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分的实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都应当属于本发明保护的范围。
实施例1
实验选取15只雄性8周c57小鼠(购自北京维通利华实验动物技术有限公司)，分为3组，每组5只，A组为对照组，采用普通食料喂养(Chow)，食料购买自北京维通利华实验动物技术有限公司，配方见表1；B组为高脂食物喂养模型组(HFD)，采用含60kcal％高脂饲料(购自Research Diets，货号D12492)，Research Diets D12492 60kcal％高脂饲料一般作为研究肥胖症和代谢综合征的标准饲料。C组采用含60kcal％高脂饲料，并每天在饮水中给予1.5g/kg小鼠体重的L-缬氨酸(V0500 Sigma-AldrichL-缬氨酸L-Valine reagent grade,纯度≥98％)，将上述L-缬氨酸粉末溶于饮水中喂养小鼠。16周后，用无菌纸收集小鼠粪便，由杭州谷禾信息技术有限公司提供16S rRNA粪便菌群测序服务。比较3组的肠道菌群Akkermansia muciniphila的丰度(图1和图2)。图1中Akkermansia muciniphila的丰度用不同灰度深浅表示，颜色越深表示Akkermansia muciniphila的丰度越高。图2中Chow表示普通食料喂养对照组，HFD代表高脂食物喂养模型组，采用含60kcal％的高脂饲料。Val代表实验组，采用含60kcal％高脂饲料，并每天在饮水中给予1.5g/kg小鼠体重的L-缬氨酸(Val)。结果发现HFD喂养16周组Akkermansia muciniphila的丰度显著低于普通食料喂养的对照组。HFD加L-缬氨酸喂养16周组Akkermansia muciniphila的丰度显著高于HFD喂养16周组，且恢复到普通食料喂养的对照组的水平。
表1普通食料喂养配方(Chow)
综上所述，可确定通过使用L-缬氨酸可以达到以下技术效果：
1、L-缬氨酸对调节Akkermansia muciniphila丰度的有效剂量为1.5g/kg/Day，在实际应用时可能因施用对象不同有所变化。
2、补充L-缬氨酸可以防止肠道Akkermansia muciniphila丰度降低，恢复Akkermansia muciniphila的丰度从而改善代谢状态。
虽然以上实验仅进行了单纯化合物的测试，但根据L-缬氨酸已知的理化性质，能够得出其制成的口服剂型均能达到以上药效，L-缬氨酸适用的剂型及相应辅料如下所述。
本发明可根据成分种类、成分含量、剂型等产生多个实施例方式。例如：
实施方式1：以L-缬氨酸为药效成分的口服液；
以口服液为例，口服液是在汤剂、注射剂基础上发展起来的新剂型，具有剂量小、吸收较快、质量稳定、携带和服用方便、易于保存的优点，其含有多种有效成分，对质量和口感有很大的影响。在不改变主要活性成分结构和功能前提下，如何能最大限度的保留有效成分、改善口感是其选用辅料的一个难点。在口服液中添加辅料可以提高口感，改善澄清度，增强稳定性，提高产品质量。
口服液常用辅料有：溶剂、芳香剂、矫味剂、澄清剂、防腐剂等，这些辅料可同时加入，也可择其一加入，其中溶剂是必加的，可以采用水。不同的辅料组合有甜味剂、芳香剂、澄清剂或防腐剂，或甜味剂和防腐剂的组合，优选甜味剂和防腐剂的组合。部分辅料兼具增甜和增香的作用，此时只需加入一种辅料即可。
针对口服液，优选地，所述甜味剂选自蛋白糖、木糖醇、阿斯巴甜和三氯蔗糖中的一种或多种。
针对口服液，优选地，所述防腐剂选自对羟基苯甲酸酯、丁基羟基茴香醚、丁基羟基甲苯和山梨酸中的一种或多种。
防腐剂可选用对羟基苯甲酸酯、丁基羟基甲苯或山梨酸，优选丁基羟基甲苯。也可以组合使用，例如羟基苯甲酸酯与丁基羟基甲苯的组合，或丁基羟基甲苯与山梨酸的组合，或对羟基苯甲酸酯与山梨酸的组合，或对羟基苯甲酸酯、丁基羟基甲苯和山梨酸的组合。
针对口服液，优选地，所述芳香剂为水果香精。
针对口服液，优选地，所述澄清剂为壳聚糖和明胶中的一种或两种混合。
实施方式2：以L-缬氨酸为药效成分的片剂；
片剂具有剂量准确，质量稳定，服用、携带及运输方便等优点。
针对片剂，所述制剂辅料包括稀释剂、粘合剂、润滑剂和崩解剂中一种或多种，优选稀释剂、粘合剂、润滑剂和崩解剂的组合。
针对片剂，优选地，所述稀释剂为纤维素类和无机盐类中的一种或多种。例如微晶纤维素、硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇等，以增加原料体积助其成型的。
针对片剂，优选地，所述粘合剂为水、乙醇、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶和聚乙烯吡咯烷酮等中的一种或多种。
针对片剂，优选地，所述润滑剂为硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇和月桂醇硫酸镁中的一种或多种。
针对片剂，优选地，所述崩解剂为低取代羟丙基、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠等中的一种或多种。
实施方式3：以L-缬氨酸为药效成分的胶囊；
在本发明中，胶囊主要提高药物的稳定性和生物利用度。所述制剂辅料为胶囊壳，所述胶囊壳为硬胶囊壳或软胶囊壳。
实施方式4：以L-缬氨酸为药效成分的颗粒剂；
颗粒剂可以直接吞服，也可以用温水冲入水中饮入，应用和携带比较方便，溶出和吸收速度较快。颗粒剂所用的制剂辅料与片剂相似，涉及填充剂、粘合剂、润湿剂、崩解剂、润滑剂和薄膜包衣材料中的一种或多种。
针对颗粒剂，优选地，所述填充剂为纤维素类和无机盐类中的一种或多种。例如微晶纤维素、硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇等，以增加原料体积助其成型的。
针对颗粒剂，优选地，所述粘合剂为水、乙醇、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶和聚乙烯吡咯烷酮等中的一种或多种。
针对颗粒剂，优选地，所述润湿剂为水或乙醇或两者的混合。例如为硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇和月桂醇硫酸镁中的一种或多种。
针对颗粒剂，优选地，所述崩解剂为低取代羟丙基、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠等中的一种或多种。
针对颗粒剂，优选地，所述薄膜包衣材料羟丙基甲基纤维素、聚乙二醇、醋酸纤维素酞酸酯和聚乙烯缩乙醛二乙胺醋酸酯中的一种或多种。
实施方式5：以L-缬氨酸为药效成分的散剂。
本发明也可制成散剂，散剂便于分剂量和服用。
以饮料为例，将本发明的组合物制成不同风味的饮料，作为日常饮品将深受欢迎。
饮料所用的制剂辅料为澄清剂、防腐剂和香味剂中的至少一种。
本发明的组合物也可制成其它散剂，例如制成功能性奶粉，加入的辅料主要为奶粉，例如脱脂奶粉，脱脂无糖奶粉。
以上多个实施方式可调整单位产品中的药剂量大小，以适应不同的用途，如药品、保健品、食品等。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.L-缬氨酸作为唯一有效成分在制备防止小鼠肠道嗜黏蛋白艾克曼菌丰度降低的药物中的应用；所述药物由L-缬氨酸与制剂辅料组成，所述制剂辅料为水；L-缬氨酸的给药剂量为1.5g/kg小鼠体重/天。
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| CN110227085A (zh) * | 2019-07-16 | 2019-09-13 | 江苏省中医院 | Akkermansia Muciniphila在制备抗抑郁药物或者保健品中的应用 |
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| WO2020043797A1 (en) * | 2018-08-29 | 2020-03-05 | Dsm Ip Assets B.V. | Formulations for improving gut health |
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